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Manipulation of colorectal polyps by biopsy, incomplete resection, or tattoo placement under the lesion has been shown to cause submucosal fibrosis and associated inferior outcomes. The effect of delays between index manipulation and definitive resection on the incidence of fibrosis is unknown. Patients undergoing EMR of previously manipulated colorectal polyps ≥10 mm from 2016 to 2021 at a tertiary referral center were included. Time from index manipulation to definitive resection and the presence of fibrosis were noted. The effects of fibrosis on EMR outcomes were assessed. Among 221 previously manipulated lesions (180 biopsy, 23 incomplete/failed resection, 1 tattoo under lesion, 17 multiple types of manipulation), 51 (23%) demonstrated fibrosis. Fibrotic lesions were found to have been resected significantly later than nonfibrotic lesions (76 vs 61 days; P =.014). In a multivariate analysis controlling for other predictors of fibrosis, each 2-week delay was associated with a 14% increase in the odds of fibrosis. Fibrotic lesions had inferior outcomes with a lower en-bloc resection rate (8% vs 24%; P =.014) and longer procedure time (71 vs 52 minutes; P <.001). Adverse event and recurrence rates were similar between groups. Delays in definitive resection of previously manipulated polyps are associated with an increased incidence of fibrosis with time and associated inferior outcomes. Manipulation should be discouraged, and if it occurs, prompt referral and scheduling for definitive resection should be prioritized. [ABSTRACT FROM AUTHOR]

The stability of the emulsified oil/water mixture depends on the strength and tightness of the interface, which is closely related to the adsorption and close packing of the active components on the interface. The core task of demulsification is to change the interface properties to enhance efficient oil-water separation. In this study, a coupling model of photo field, thermo field, and electro field was constructed to focus on fully considering the particularity of the demulsification, while improving the utilization efficiency of solar energy by presetting and matching a variety of energy flows and sub-processes. Taking oil/water emulsion from the ASP flooding as an example , the oil removal rate of 82.27% can be obtained, and efficient energy modes, namely high-intensity thermo field, uniform photo field and low-intensity electro field, are established. At the same time, the results show that the photo-thermo-electro field changes the properties of the oil-water interface, such as the interfacial tension, zeta potential and modulus. The mechanism of solar demulsification is that the solar thermal effect changes the motion state of the molecules at the interface, the coupling electro effect drives the migration of charged droplets and the stretching or deformation of the polymer chain, which combined with the photo field to degrade the polymer at the interface. Solar demulsification not only enables innovation in the form of energy and promotes its sustainable development, but also provides a green process in which solar thermo, photo, and electro are synergistically combined to achieve demulsification. • A new process of solar utilization is conducted. • Solar energy efficiency and demulsification is synergistically coupled. • The demulsification can be characteristically and favorably controlled. • The focus of demulsification is to change the properties of the oil-water interface. • A green and efficient separation of emulsified oil/water mixtures can be achieved. [ABSTRACT FROM AUTHOR]

Cinnamon is widely used as a medicinal herb and a culinary spice. The major bioactive component of cinnamon is cinnamon essential oil (CEO). CEO has been reported to have anti-inflammatory and antioxidant effects, but its mechanism of action is not known. In this study, metabolomics was combined with "weighting coefficients" from network pharmacology to identify key pathways and targets, differential metabolites and key metabolic pathways for the therapeutic effects of CEO on Hyperuricemia (HUA), and to precisely investigate the molecular mechanisms of the therapeutic effects of CEO on HUA. Metabolomic analysis revealed that abnormal l -glutamate metabolism and dysregulation of Arachidonic acid (AA) metabolic pathways exacerbated inflammatory responses and oxidative stress, subsequently mediating pathological changes in HUA and exacerbating renal tissue damage. Pharmacodynamic validation showed that CEO alleviated the renal inflammatory response by inhibiting hepatic xanthine oxidase activity, upregulating superoxide dismutase and glutathione peroxidase levels, and downregulating malondialdehyde levels, synergistically inhibiting NLRP3 inflammasome activation, suppressing downstream inflammatory Interleukin-1 beta (IL-1β) and Interleukin-18 (IL-18) secretion, and enhancing antioxidant levels. Additionally, CEO exerted renal protective effects by upregulating the renal transporters OAT1 and ABCG2 and downregulating the GLUT9 and URAT1 levels, resulting in the downregulation of uric acid production and the alleviation of renal tubular lesions. This suggests that CEO could be considered as a potential functional food for kidney damage caused by hyperuricemia. [ABSTRACT FROM AUTHOR]

[Display omitted] • Amide group was introduced to prepare PBAHX for chalcopyrite and pyrite flotation. • The introduction of amide group significantly reduced the odor of xanthate. • PBAHX exhibited superior selectivity for chalcopyrite against pyrite than SIBX. • Horizontal adsorption model was established to account for flotation differences. Xanthate, due to its superior collecting ability, is widely used in the field of minerals flotation. However, its weak selectivity and foul odor make it difficult to separate chalcopyrite from pyrite and reduce pollution. This work provides an efficient and odorless collector to selectively separate chalcopyrite from pyrite. Amide group was introduced into xanthate and an efficient and odorless xanthate derivative was designed, potassium O-(6-(butylamino)-6-oxohexyl) xanthate (PBAHX), to selectively separate chalcopyrite and pyrite. The flotation results showed that PBAHX exhibited superior selectivity, the separation index of PBAHX for chalcopyrite and pyrite is 2.65 while that of the traditional sodium isobutyl xanthate (SIBX) is 1.29, and enabled the separation of chalcopyrite and pyrite. The electronic-nose detection demonstrated that the odor intensity of PBAHX was lower than SIBX. Subsequently, "horizontal" adsorption model was formed for the adsorption of PBAHX on pyrite to explain the differences in flotation results. Besides, hydrogen bonds may be produced between collector molecules to dampen odor. PBAHX shows potential as a green and effective alternative to sulfide mineral flotation. [ABSTRACT FROM AUTHOR]

A fast preconditioned policy iteration method is proposed for the Hamilton–Jacobi–Bellman (HJB) equation involving tempered fractional order partial derivatives, governing the valuation of American options whose underlying asset follows exponential Lévy processes. An unconditionally stable upwind finite difference scheme with shifted Grünwald approximation is first developed to discretize the established HJB equation under the tempered fractional diffusion models. Next, the policy iteration method as an outer iterative method is utilized to solve the discretized HJB equation and proven to be convergent in finite steps to its numerical solution. Given the Toeplitz-like structure of the coefficient matrix in each policy iteration, the resulting linear system can be fast solved by the Krylov subspace method as an inner iterative method via fast Fourier transform (FFT). Furthermore, a novel preconditioner is proposed to speed up the convergence rate of the inner Krylov subspace iteration with theoretical analysis to ensure the linear system can be solved in O ( N log N ) operations under some mild conditions, where N is the number of spatial node points. Numerical examples are given to demonstrate the accuracy and efficiency of the proposed fast preconditioned policy method. [ABSTRACT FROM AUTHOR]

Many hormonal and environmental signals regulate common cellular and developmental processes in plants. While the molecular pathways that transduce these signals have each been studied in detail, how these pathways are wired into regulatory networks to provide the coordinated responses has remained an outstanding question. Recent studies of the brassinosteroid signaling network have revealed extensive signal integration through direct interactions between components of different signaling pathways. In particular, a circuit of interacting transcription regulators integrates many signaling pathways to enable coordinated and coherent regulation of seedling morphogenesis by hormonal and environmental signals. The recent studies support an emerging theme that complex networks of highly integrated signaling pathways underlie the high levels of developmental plasticity and environmental adaptability of plants. [ABSTRACT FROM AUTHOR]

Abstract: This study examines the geographical variations of self-rated health of the elderly based on the 2008 Chinese Longitudinal Healthy Longevity Survey. Multilevel logistic models are employed to estimate how individual, family, and institutional factors affect the health of the elderly at both individual and province levels. Results show that while individual characteristics help to explain self-rated health, the family remains an important determinant. Those with nobody to care for them, those in poverty and those who have to rely on medical insurance report the worst health. The role of the state is relatively limited in contributing to the health of the elderly. There are substantial between province differences. [Copyright &y& Elsevier]

Abstract: In the last three decades, China has experienced rapid economic development and growing economic inequality, such that economic disparities between rural and urban areas, as well as coastal and interior areas have deepened. Since the late 1990s China has also experienced an ageing population which has attracted attention to the wellbeing of the rapidly growing number of elderly. This research aims to characterise province differences in health and to explore the effects of individual income and economic disparity in the form of income inequality on health outcomes of the elderly. The study is based on the Chinese Longitudinal Healthy Longevity Survey data collected in 2008 for 23 provinces. Multilevel logistic models are employed to investigate the relationship between income, income inequality and self-rated health for the elderly using both individual and province-level variables. Results are presented as relative odds ratios, and for province differentials as Median Odds Ratios. The analysis is deliberately exploratory so as to find evidence of income effects if they exist and particular attention is placed on how province-level inequality (contemporaneous and lagged) may moderate individual relationships. The results show that the health of the elderly is not only affected by individual income (the odds of poor health are 3 times greater for the elderly with the lowest income compared to those at the upper quartile) but also by a small main effect for province-level income inequality (odds ratio of 1.019). There are significant cross-level interactions such that where inequality is high there are greater differences between those with and without formal education, and between men and women with the latter experiencing poorer health. [Copyright &y& Elsevier]

Abstract: A single gene deletion causes lack of leptin and obesity in B6.V-Lepob (obese; ob) mice compared with wild-type C57BL/6J (B6) mice. This study compared the phenotype of nociception and supraspinal antinociception in obese and B6 mice by testing 2 hypotheses: (1) microinjection of cholinomimetics or an adenosine receptor agonist, but not morphine, into the pontine reticular formation (PRF) is antinociceptive in B6 but not obese mice, and (2) leptin replacement in obese mice attenuates differences in nociceptive responses between obese and B6 mice. Adult male mice (n = 22) were implanted with microinjection guide tubes aimed for the PRF. The PRF was injected with neostigmine, carbachol, nicotine, N 6-p-sulfophenyladenosine (SPA), morphine, or saline (control), and latency to paw withdrawal (PWL) from a thermal stimulus was recorded. B6 and ob mice did not differ in PWL after saline microinjection into the PRF. Neostigmine, carbachol, and SPA caused PWL to increase significantly in B6 but not obese mice. An additional 15 obese mice were implanted with osmotic pumps that delivered leptin for 7 days. Leptin replacement in obese mice restored the analgesic effect of PRF neostigmine to the level displayed by B6 mice. The results show for the first time that leptin significantly alters supraspinal cholinergic antinociception. Perspective: This study specifies a brain region (the pontine reticular formation), cholinergic neurotransmission, and a protein (leptin) modulating thermal nociception. The results are relevant for efforts to understand the association between obesity, disordered sleep, and hyperalgesia. [Copyright &y& Elsevier]

Abstract: Exercise and stress are known to influence pain perception. However, little is known about how level of fitness influences pain perception and the experience of pain. In the present study, pain perception before and after exercise to exhaustion was examined in 6 rats systematically bred to have a high aerobic capacity (HCR animals) and 6 rats systematically bred to have a low aerobic capacity (LCR animals). HCR animals had significantly higher pain thresholds compared to LCR animals before and after exercise (7.66s compared to 6.01s, t =−3.07, p <0.05; and 6.89s versus 4.73s, t =−3.73, p <0.01, respectively). In addition, both groups of animals displayed evidence of hyperalgesia following exercise compared to baseline. However, the pain thresholds of HCR animals returned to baseline levels faster than LCR animals following exercise. The findings support the hypothesis that level of fitness plays a role in the perception of pain. In addition, a higher level of fitness may serve as buffer against the effects of stress and help to reduce or prevent the experience of clinical pain. Further research is needed to examine the mechanisms that underlie this phenomenon. [Copyright &y& Elsevier]

The safety and efficacy of tofacitinib in Crohn's disease (CD) has been studied in 2 phase II trials in patients with moderate-to-severe CD with no new safety signals observed, but no significant difference from placebo in the primary efficacy endpoint of clinical response.1–3 However, post hoc analyses and smaller studies have observed clinical and biologic response to tofacitinib in patients with CD.2,4,5 There is a paucity of real-world effectiveness and safety data for tofacitinib in non–Food and Drug Administration label usage in patients with CD and patients with inflammatory bowel disease–unclassified (IBD-U). [ABSTRACT FROM AUTHOR]

Based on a survey in seven provinces and drawing on previous evidence of in situ urbanization in the coastal areas, this paper examines the implications of return migration for in situ urbanization of migrants' sending areas in China. It shows that returnees can act as catalysts for in situ urbanization by bringing back entrepreneurship, accrued human, financial, social, cultural and technological capital to facilitate rural-urban socioeconomic transformation of their home areas. The results of logistic regressions further confirm that returnees' individual characteristics and migration occupations significantly increase their probability of engaging in non-agricultural occupations post return. However, they seem to have little impact on returnees' likelihood of working in local urban areas. The results suggest that even though return migrants have exhibited somewhat positive impacts on the development of their home areas, their role is rather limited in promoting in situ rural-urban transformation. A weak industrial base at the origin has been identified as a major barrier for rural-urban transformation, which suggests that strategic measures to strengthen industrial capacity in those migrant sending areas should take place in order to fully unleash return migrants' potential in stimulating in situ urbanization of their home areas. • Returnees can serve as catalysts for in situ urbanization of their home areas. • Returnees bring back human, financial, social, and cultural capital as well as entrepreneurship to rural areas. • Individual characteristics and migration occupation significantly affect returnees' uptake of non-farm occupations. • However, their effects on returnees' likelihood to work in local urban areas are not significant. • Weak industrial base is a major barrier to returnees' contribution to in situ urbanization. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor (TNF) is essential for the host defense against tuberculosis (TB). However, scarcity or excessive TNF production in macrophages can also increase susceptibility to TB. The precise mechanisms underlying how Mycobacterium tuberculosis (Mtb) induces TNF over-expression are unclear. Here, we show that Mtb infection significantly increases 5-hydroxylmethylocytosine (5hmC) levels in the TNF promoter. Luciferase reporter assays identify the precise methylated CpG sites that are essential to regulating TNF promoter activity. Infection simultaneously promotes the expression of the TET2 demethylase in macrophages. After inhibiting NF-κB or knocking down TET2, we found that TNF promoter demethylation levels is increased while Mtb -induced TNF expression decrease. Here, NF-κB binds to TET2 and mediates its recruitment to the TNF promoter to induce TNF demethylation. Finally, we show that TLR2 activation during Mtb infection promotes NF-κB translocation into the nucleus which is important for NF-κB-mediated TET2-dependent TNF promoter demethylation thus helps drive Mtb -induced TNF expression. Targeting this axis might be a novel strategy for host-directed therapy against TB. [ABSTRACT FROM AUTHOR]

This study aimed to explore the neural activity associated with the Working Memory (WM) Stroop effect. Stroop facilitation and interference effects in WM were also investigated by adding a neutral condition to the WM Stroop paradigm. In each trial, participants were first asked to remember a word in WM, then respond to the color of the subsequent rectangle. The word meaning and rectangular color were congruent, incongruent, or irrelevant (neutral). Finally, a probe word appeared and participants judged whether it was the same as the first presented word. For the color decision task, behavioral results showed that 1) RTs were longer for the incongruent than congruent condition, indicating a WM Stroop effect; 2) RTs were shorter for the congruent than neutral condition, indicating a WM Stroop facilitation effect; and 3) RTs were shorter for the incongruent than neutral condition, indicating no Stroop interference effect in WM. ERPs locked to the rectangle revealed that 1) greater N2 and P3 activity was evoked for the incongruent than congruent condition, indicating more intensive conflict detection and conflict resolution processes for the incongruent condition; and 2) enhanced N2 but decreased P3 components were evoked for the neutral than the congruent and incongruent conditions, indicating a more intensive conflict monitoring process but decreased conflict resolution process for the neutral condition. These results demonstrate that when WM content is congruent with the attention task, it can facilitate attention, but WM content may not interfere with attention when they are incongruent. • A neutral condition was added in the WM Stroop effect paradigm. • No WM Stroop interference effect was found at long SOA. • Enhanced N2 component was evoked for incongruent than congruent condition. • Congruent WM content with attention task facilitates individuals' response. [ABSTRACT FROM AUTHOR]

3D flower-like architecture (P, W)-MoO 2 /NF is employed as an efficient bifunctional catalyst for overall water splitting in 1.0 M KOH. • Flower-like architecture (P, W)-MoO 2 /NF is assembled on 3D nickel foam substrate. • Unique flower-like architecture is responsible for enhanced activity. • Synergistic electron interactions is beneficial to electrocatalytic properties. Due to the rapid consumption of fossil fuels and serious environmental pollution from nonrenewable energy, developing highly efficient, stable and earth-abundant bifunctional electrocatalysts for overall water splitting is thereby an urgent need but remains a significant challenge. Heteroatom doping is regarded as an effective tactic to facilitate electron interactions, and thereby enhance the electrocatalytic activity. In this work, (P, W)-codoped MoO 2 nanoflowers were successfully assembled on a nickel foam (NF) substrate (marked as (P, W)-MoO 2 /NF) by hydrothermal and phosphorization processes. The as-prepared catalyst (P, W)-MoO 2 /NF exhibits excellent catalytic activities with lower overpotentials of 308 mV and 89 mV to deliver 40 mA cm−2 for oxygen evolution reaction (OER) and 10 mA cm−2 for hydrogen evolution reaction (HER), respectively. More significantly, when directly assembled in the electrolyzer as a bifunctional electrocatalyst for overall water splitting, it only requires a cell voltage of 1.65 V to deliver a current density of 30 mA cm−2. The as-prepared catalyst (P, W)-MoO 2 /NF also displays splendid long-term stability over 20 h without a visible decrease in an alkaline solution. The blooming flower-like architecture can afford abundant active sites, and the doping of heteroatoms can tune the electronic transfer, which are both responsible for the enhancement in the electrocatalytic properties. This work provides a unique direction to the rational design and synthesis of highly efficient and stable non-noble metal molybdenum-based bifunctional electrocatalysts for overall water splitting. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor 21 (FGF21) is a hormone secreted predominantly in the liver, pancreas and adipose tissue. Recently, it has been reported that FGF21-Transgenic mice can extend their lifespan compared with wild type counterparts. Thus, we hypothesize that FGF21 may play some roles in aging of organisms. In this study d -galactose ( d -gal)-induced aging mice were used to study the mechanism that FGF21 protects mice from aging. The three-month-old Kunming mice were subcutaneously injected with d -gal (180 mg·kg − 1 ·d − 1 ) for 8 weeks and administered simultaneously with FGF21 (1, 2 or 5 mg·kg − 1 ·d − 1 ). Our results showed that administration of FGF21 significantly improved behavioral performance of d -gal-treated mice in water maze task and step-down test, reduced brain cell damage in the hippocampus, and attenuated the d -gal-induced production of MDA, ROS and advanced glycation end products (AGEs). At the same time, FGF21 also markedly renewed the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and total anti-oxidation capability (T-AOC), and decreased the enhanced total cholinesterase (TChE) activity in the brain of d -gal-treated mice. The expression of aldose reductase (AR), sorbitol dehydrogenase (SDH) and member-anchored receptor for AGEs (RAGE) declined significantly after FGF21 treatment. Furthermore, FGF21 suppressed inflamm-aging by inhibiting IκBα degradation and NF-κB p65 nuclear translocation. The expression levels of pro-inflammatory cytokines, such as TNF-α and IL-6, decreased significantly. In conclusion, these results suggest that FGF21 protects the aging mice brain from d -gal-induced injury by attenuating oxidative stress damage and decreasing AGE formation. [ABSTRACT FROM AUTHOR]

This study undertakes a survival analysis of elderly persons in China using Chinese Longitudinal Healthy Longevity Survey 2002–2008. Employing discrete-time multilevel models, we explored the effect of social support on the survival of elderly people in China. This study focuses on objective (living arrangements and received support) and subjective activities (perceived support) of social support, finding that the effect of different activities of social support on the survival of elderly people varies according to the availability of different support resources. Specifically, living with a spouse, financial independence, perceiving care support from any resource is associated with higher survival rates for elderly people. Separate analysis focusing on urban elderly and rural elderly revealed broadly similar results. There is a larger difference between those perceiving care support from family or social service and not perceiving care support in urban areas comparing to those in rural areas. Those who cannot pay medical expenses are the least likely to survive. The higher level of economic development in province has no significant effect on the survival of elderly people for the whole sample model and the elderly people in urban areas; however, there is a negative influence on the survival of the rural elderly people. [ABSTRACT FROM AUTHOR]

[Display omitted] • Breakthrough times of gas mixture in MOFs are batch calculated. • Δ T is employed to screen MOFs with superior gas separation performance. • Extreme gradient boosting achieves accurate results in predicting Δ T. • The PLD&LCD, along with K , play a key role in the gas separation process. • Transition metals have the highest proportion of metal center types in TOP 100 MOFs. In the field of metal–organic frameworks (MOFs) screening studies, the batch calculation of the mixed gas breakthrough time difference (Δ T i) in MOFs and its intricate correlation with various descriptors remain underexplored. This research undertook batch calculations of the breakthrough curves (BC) for different gases within a simulated natural gas environment, designating Δ T i as the performance metric for MOFs in gas separation. The separation performance of computation-ready experimental MOFs for CH 4 /C 2 H 6 and CH 4 /CO 2 mixtures was analyzed in depth utilizing machine learning (ML)-assisted high-throughput computational screening (HTCS) techniques. Then, five ML algorithms were used to quantify the relationship between MOF descriptors and performance, and the effect of the metal center site on the separation performance was further explored. Ultimately, the top ten MOFs were selected for each system. Combining HTCS, ML, and BC, this work provides fresh insights for understanding and designing MOFs with customized adsorption and separation properties. [ABSTRACT FROM AUTHOR]

In recent years, fractional partial differential equation (FPDE) has been widely applied in options pricing problems, which better explains many important empirical facts of financial markets. However, the vast majority of the literatures focus on pricing the single asset option under the FPDE framework. In this paper, a two-dimensional FPDE governing the valuation of rainbow options is established, where two underlying assets are assumed to follow independent exponential Lévy processes, and its boundary conditions are determined by solving one-dimensional FPDEs. A second-order accurate finite difference scheme is proposed to discretize the two-dimensional FPDE. Given the block Toeplitz with Toeplitz block structure of the coefficient matrix, a fast preconditioned Krylov subspace method is developed for solving the resulting linear system with O (N log N) computational complexity per iteration, where N is the matrix size. The proposed preconditioner accelerates the convergence of the iterative method with theoretical analysis. Numerical examples are given to demonstrate the accuracy and efficiency of our proposed numerical methods. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the mechanism through which rosemary essential oil treats atopic dermatitis. A dinitrochlorobenzene (DNCB)-induced atopic dermatitis mouse model was established and treated with low (1%), medium (2%), and high (4%) doses of Rosmarinus officinalis essential oil (EORO). Serum levels of interleukin (IL)−6 and tumor necrosis factor-alpha (TNF-α) in each group were determined using enzyme-linked immunosorbent assay (ELISA). Skin tissues were stained with hematoxylin-eosin and toluidine blue. We used network pharmacology and molecular docking techniques to verify the biological activity of essential proteins and their corresponding compounds in the pathway. Gas chromatography-mass spectrometry (GC-MS) was used for metabolomics analysis and multivariate statistical analysis of mouse serum to screen differential metabolites and metabolic pathway analysis. Protein expression of p-JAK1, CD4+ cells, and IL-4 in the skin tissue was detected by immunohistochemistry analysis. Protein levels of STAT3, p-STAT3, P65, and p-P65 in damaged skin tissues were detected using western blotting. The skin of mice in the model group showed different degrees of erythema, dryness, scratches, epidermal erosion and shedding, and crusting. After treatment, the serum levels of IL-6 and TNF-α in EORO group were significantly decreased, and the expression of p-JAK1,CD4 + cells, IL-4, p-P65 / P65 and p-STAT3 / STAT3 proteins in skin tissues were decreased. EORO can effectively improve DNCB-induced AD-like skin lesions in mice by regulating the JAK/STAT/NF-κB signaling pathway, thereby reducing the production of downstream arachidonic acid metabolites, inhibiting skin inflammation, and restoring epidermal barrier function. [Display omitted] [ABSTRACT FROM AUTHOR]

Pulmonary fibrosis (PF) is a chronic, progressive lung disease, characterized by excessive matrix formation, destruction of the normal lung architecture, dysfunction and finally death. Fibroblast growth factor 21 (FGF21) is a promising pleiotropic regulator in glucolipid metabolism. Recently, we reported that FGF21 attenuates hepatic fibrogenesis. However, the role of FGF21 on PF is unknown. In this study, mice endotracheal instilled with bleomycin (BLM) were used to study the effect of FGF21 on PF. Bleomycin-instilled mice were administered with pirfenidone (PFD) or FGF21 daily for 3 weeks from 7 days after instillation of BLM. Results showed FGF21 and PFD attenuated the dense deposition of collagen, intense infiltration of inflammatory cells and destruction of tissue architecture in lungs caused by BLM, and also alleviated the increased expression of TGF-β, Col I and α-SMA and decreased the expression of E-cadherin. At the same time, FGF21 also markedly reversed the activity of SOD and T-AOC, decreased the enhanced content of MDA and increased the expression of Nrf-2 in the lungs of BLM-treated mice. To further explore the mechanisms of FGF21 attenuate PF by amelioration of oxidative stress, we examined the effect of FGF21 in A549 cells treated with paraquat (PQ). A549 cells were incubated with PQ plus FGF21 or PFD for 48 h. The results showed that FGF21 and PFD reduced the expression of TGF-β, Col I and α-SMA and increased the expression of E-cadherin in PQ-treated A549 cells. FGF21 also suppressed oxidative stress in PQ-treated A549 cells, as evidenced by a decrease of the MDA level, a reversed activity of antioxidant enzymes and an increased expression of Nrf-2. We conclude that FGF21 inhibits pulmonary fibrosis through activating Nrf-2 pathway, subsequently suppressing oxidative stress, inhibiting ECM deposition and pulmonary fibrogenesis, suggesting that FGF21 has potential as therapeutic agent for treatment of pulmonary fibrosis. [ABSTRACT FROM AUTHOR]

Recently, targeting inflammatory cytokines in the pathogenic process of rheumatoid arthritis is now performed as a feasible biological method in therapy. However, treatments against single cytokine are often difficult to achieve the ideal therapeutic effect. Multi-target drugs permit more effective suppression of inflammation. In this study, we constructed an IgG-like bispecific antibody targeting IL-1β and IL-17A and expressed it in mammalian cells. The therapeutic efficacy was studied in CIA (collagen-induced arthritis) mice, which were administrated with either FL-BsAb1/17 (IgG-like bispecific antibody targeting IL-1β and IL-17A) or monovalent IL-1β Mab or IL-17A Mab (anti-IL-1β/IL-17A monoclonal antibody). We noticed that FL-BsAb1/17 had better effect on alleviating clinical symptom by significantly lowering arthritis score and relieving histological lesion on aspect of less damnification in synovial hyperplasia and cartilage destruction than monovalent Mab alone. In addition, FL-BsAb1/17 was more potent in inhibiting IL-1β, IL-17A, IL-6, TNF-α and anti-CCP antibody in the serum and in down-regulating the expression of IL-1β, IL-17A, IL-6, TNF-α, MMP-3 and RANKL in the spleen, compared to monovalent Mab alone. Further, the anti-inflammatory effect of FL-BsAb1/17 was demonstrated by significantly depressing Th17 cells expansion through decreasing phosphorylated STAT3 in the spleen of the CIA mice. FLS (fibroblast-like synoviocytes) from RA patients were used to examine the therapeutic efficacy of FL-BsAb1/17 in human pathological tissue. FL-BsAb1/17 could significantly decrease the production of IL-6 induced by IL-1β and/or IL-17A in FLS. In conclusion, FL-BsAb1/17 has the possibility to be a promising therapeutic agent for RA. [ABSTRACT FROM AUTHOR]

It has been demonstrated that circulating FGF21 levels are elevated in the serum and synovial fluid of patients with rheumatoid arthritis (RA). The aim of this study is to investigate efficacy of FGF21 for treatment of RA and the molecular mechanisms of the therapeutic effect on collagen-induced arthritis (CIA). Mice with CIA were subcutaneously administered with FGF21 (5, 2 or 1 mg·kg − 1 ·d − 1 ), IL-1β antibody (5 mg·kg − 1 ·d − 1 ), IL-17A antibody (5 mg·kg − 1 ·d − 1 ) and dexamethasone (DEX) (1 mg·kg − 1 ·d − 1 ), respectively. The effects of treatment were determined by arthritis severity score, histological damage and cytokine production. The activation of NF-κB was analyzed by Western blotting. We also detected the levels of oxidative stress parameters. Our results showed that FGF21 had beneficial effects on clinical symptom and histological lesion of CIA mice. Similar to antibody and DEX, FGF21 treatment alleviated the severity of arthritis by reducing humoral and cellular immune responses and down-regulating the expression of pro-inflammatory cytokines. FGF21 treatment also reduced the expression of TNF-α, IL-1β, IL-6, IFN-γ and MMP-3 and increased level of IL-10 in the spleen tissue or the plasma of CIA mice in a dose-dependent manner. Furthermore, FGF21 inhibited IκBα degradation and NF-κB p65 nuclear translocation and induced significant changes of oxidative stress parameters (MDA, SOD, CAT, GSH-PX and GSH) in the plasma. FGF21 exerts therapeutic efficacy for RA through antioxidant reaction and inhibiting NF-κB inflammatory pathway. This study provides evidence that FGF21 may be a promising therapeutic agent for RA patients. [ABSTRACT FROM AUTHOR]

Abstract: Interleukin-1β (IL-1β) and interleukin-17A (IL-17A) are inducible factors and important cytokines in the pathogenesis of rheumatoid arthritis (RA). In the present study, three bispecific and neutralizing antibodies (BsAB-1, BsAB-2 and BsAB-3) against both hIL-1β and hIL-17A were constructed, their therapeutic efficacy was compared on collagen induced arthritis (CIA) model mice. In vitro assays demonstrated that the three antibodies could simultaneously bind to target both hIL-1β and hIL-17A. Mice with CIA were subcutaneously administered with one of three antibodies every two days for 29days, we noticed that, compared with the BsAB-2 and BsAB-3, BsAB-1 antibody therapy resulted in more significant effect on alleviating the severity of arthritis by preventing bone damage and cartilage destruction and substantially decreasing production of CII-specific antibodies. In addition, BsAB-1 antibody was more potent in the inhibition of mRNA expression of IL-2, IL-1β, IL-17A, TNF-α and MMP-3 in the spleen of CIA mice compared to the other two. In summary, BsAB-1 is superior over BsAB-2 and BsAB-3 for the treatment of RA model mice, and may be chosen as an ideal candidate for further development of therapeutic drugs for treatment of RA. [Copyright &y& Elsevier]